Orally disintegrative dosage form

ABSTRACT

The present invention features an orally disintegrating dosage form including from about 5% to about 40%, by weight, of at least one hydrated salt and a pharmaceutically active agent, wherein the at least hydrated salt has a dehydration temperature of from about 20 to about 120° C.

BACKGROUND OF THE INVENTION

Pharmaceuticals intended for oral administration are typically providedin solid form as tablets, capsules, pills, lozenges, or granules.Tablets are swallowed whole, chewed in the mouth, or dissolved in theoral cavity. Soft tablets that either are chewed or dissolve in themouth are often employed in the administration of pharmaceuticals whereit is impractical to provide a tablet for swallowing whole. Withchewable tablets, the act of chewing helps to break up the tabletparticles as the tablet disintegrates and may increase the rate ofabsorption by the digestive tract. Soft tablets are also advantageouswhere it is desirable to make an active ingredient available topicallyin the mouth or throat for local effects and/or systemic absorption.Soft tablets are also utilized to improve drug administration inpediatric and geriatric patients. Soft tablets designed to disintegratein the mouth prior to swallowing are particularly useful for improvingcompliance of pediatric patients.

It has now been discovered that an orally disintegrating dosage form canbe made from a mixture comprising at least one pharmaceutically activeagent and at least one hydrated salt. Such process allows for themanufacture of dosage from (such as tablets) without the need of acompression or lyophillization processing step, which in turn, mayassist in coated or taste-masked pharmaceutically active agentcontaining particles remaining intact during the manufacturing process.

SUMMARY OF THE INVENTION

In one aspect, the present invention features an orally disintegratingdosage form including from about 5% to about 40%, by weight, of at leastone hydrated salt and a pharmaceutically active agent, wherein the atleast hydrated salt has a dehydration temperature of from about 20 toabout 120° C.

The present invention also features a process for making an orallydisintegrating dosage form including the steps of: a) providing a unitproduct sheet having a recess in a desired shape and volume suitable forcontaining said orally disintegrating dosage form; b) introducing intothe recess a predetermined amount of a flowable material comprising atleast about 5%, by weight, of at least one hydrated salt and apharmaceutically active agent, wherein said at least one hydrated salthas a dehydration temperature of from about 20 to about 120° C.; c)heating the material in the recess to a temperature above saiddehydration temperature for said at least one hydrated salt and for asufficient period of time to cause the material to fuse into anaggregate, and d) cooling the aggregate in the recess so that theaggregate solidifies into the orally dissolving dosage form suitable forconsumption.

The present invention also features a dosage form comprising an edibleouter portion and an orally disintegrating portion, the edible outerportion containing the orally disintegrating portion and the orallydisintegrating portion including at least about 5%, by weight, of atleast one hydrated salt and a pharmaceutically active agent, wherein theat least one hydrated salt has a dehydration temperature of from about20 to about 120° C.;

The present invention also features a process for making a dosage formcomprising an edible outer portion and an orally disintegrating portionincluding the steps of: a) preparing an edible outer portion having arecess in a desired shape and volume suitable for containing the orallydisintegrating portion of said dosage form; b) introducing into therecess a predetermined amount of a flowable material comprising at leastabout 5%, by weight, of at least one hydrated salt and apharmaceutically active agent, wherein said at least one hydrated salthas a dehydration temperature of from about 20 to about 120° C.; c)heating the material in the recess to a temperature above saiddehydration temperature for said at least one hydrated salt and for asufficient period of time to cause the material to fuse into anaggregate, and d) cooling the aggregate in the recess so that theaggregate solidifies into the orally dissolving dosage form suitable forconsumption.

Other features and advantages of the present invention will be apparentfrom the detailed description of the invention and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based upon thedescription herein, utilize the present invention to its fullest extent.The following specific embodiments can be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference. As used herein, all percentages are by weightunless otherwise specified.

Orally Disintegrative Dosage Form

The orally disintegrative dosage form of the present invention includesat least one hydrated salt and a pharmaceutically active agent, andoptionally includes one or more carbohydrates, effervescent couples,flavorants, and other ingredients.

In one embodiment, the orally disintegrative dosage form has a hardnessof less than about 15 kp/cm², such as less than 10 kp/cm², such as lessthan 5 kp/cm². In one embodiment a sufficient amount of energy isapplied to the orally disintegrative dosage form for a sufficient amountof time to increase its hardness. In one embodiment, energy is appliedto the orally disintegrative dosage form in the form of heat orelectromagnetic radiation, such as microwaves. Depending on thecomposition of the disintegrative dosage form, in one embodiment,heating may be performed at a temperature generally in the range ofambient temperature to 100° C. or beyond for a time sufficient toachieve a fusing and/or hardening effect.

In one embodiment, the orally disintegrative dosage form has afriability of less than about 2% (such as less than about 1%, such asless than about 0.5%) following to the application of energy to theflowable material in order to create the disintegrative dosage form,which is the second step of the process. A discussion of orallydisintegrative dosage form friability is presented in USP 23 (1995)1216, p. 1981.

In one embodiment the orally disintegrative dosage form is designed todisintegrate in the mouth when placed on the tongue in less than about60 seconds, e.g. less than about 45 seconds, e.g. less than about 30seconds, e.g. less than about 15 seconds.

Hydrated Salt

The orally disintegrating dosage form, or orally disintegrating dosageportion, includes at least one hydrated salt. Examples of hydrated saltsinclude, but are not limited to, sodium sulfate hydrate, sodiumcarbonate hydrate, calcium chloride hydrate, sodium hydrogen phosphatehydrate, and mixtures thereof. In one embodiment, the hydrated salt hasmolecular weight from about 150 to about 400 daltons, such as from about200 to about 350 daltons. In one embodiment, the dosage form/portioncomprises from about 5% to about 40%, by weight, of at least onehydrated salt, such as from about 5% to about 20%, by weight.

Carbohydrate

In one embodiment, the orally disintegrating dosage form includes atleast 40%, by weight, of at least one carbohydrate. Examples ofcarbohydrates include, but are not limited to: sugars such as dextrose,dextrose monohydrate, lactose, glucose, fructose, maltodextrin, isomalt,sucrose, corn syrup solids and mannose; carbohydrate alcohols, such assugar alcohols such as hydrogenated starch hydrolysates such assorbitol, lactitol, xylitol, erythritol, mannitol, and polyols; andmixtures thereof. In certain embodiments the dosage form comprises atleast 40% by weight, such as at least 60% by weight, of at least onecarbohydrate.

In one embodiment the weight ratio of said at least one hydrated salt tosaid at least one carbohydrate is from about 1:4 to about 1:30, such asfrom about 1:9 to about 1:20.

Water Insoluble Fillers

In one embodiment the orally disintegrating dosage form/portion issubstantially free of a directly compressible water insoluble filler.Water insoluble fillers include but are not limited to, microcrystallinecellulose, directly compressible microcrystalline cellulose, celluloses,water insoluble celluloses, starch, cornstarch and modified starches. Asdescribed in this embodiment substantially free is less than 2 percent,e.g. less than 1 percent or completely free.

Pharmaceutically Active Agent

The dosage form of the present invention includes at least onepharmaceutically active agent. What is meant by a “pharmaceuticallyactive agent” is an agent (e.g., a compound) that is permitted orapproved by the U.S. Food and Drug Administration, European MedicinesAgency, or any successor entity thereof, for the oral treatment of acondition or disease. Suitable pharmaceutically active agents include,but are not limited to, analgesics, anti-inflammatory agents,antihistamines, antibiotics (e.g., antibacterial, antiviral, andantifungal agents), antidepressants, antidiabetic agents,antispasmodics, appetite suppressants, bronchodilators, cardiovasculartreating agents (e.g., statins), central nervous system treating agents,cough suppressants, decongestants, diuretics, expectorants,gastrointestinal treating agents, anesthetics, mucolytics, musclerelaxants, osteoporosis treating agents, stimulants, nicotine, andsedatives.

Examples of suitable gastrointestinal treating agents include, but arenot limited to: antacids such as aluminum-containing active ingredients(e.g., aluminum carbonate, aluminum hydroxide, dihydroxyaluminum sodiumcarbonate, and aluminum phosphate), bicarbonate-containing activeingredients, bismuth-containing active ingredients (e.g., bismuthaluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate,and bismuth subnitrate), calcium-containing active ingredients (e.g.,calcium carbonate), glycine, magnesium-containing active ingredients(e.g., magaldrate, magnesium aluminosilicates, magnesium carbonate,magnesium glycinate, magnesium hydroxide, magnesium oxide, and magnesiumtrisilicate), phosphate-containing active ingredients (e.g., aluminumphosphate and calcium phosphate), potassium-containing activeingredients (e.g., potassium bicarbonate), sodium-containing activeingredients (e.g., sodium bicarbonate), and silicates; laxatives such asstool softeners (e.g., docusate) and stimulant laxatives (e.g.,bisacodyl); H2 receptor antagonists, such as famotidine, ranitidine,cimetadine, and nizatidine; proton pump inhibitors such as omeprazoleand lansoprazole; gastrointestinal cytoprotectives, such as sucraflateand misoprostol; gastrointestinal prokinetics such as prucalopride;antibiotics for H. pylori, such as clarithromycin, amoxicillin,tetracycline, and metronidazole; antidiarrheals, such as bismuthsubsalicylate, kaolin, diphenoxylate, and loperamide; glycopyrrolate;analgesics, such as mesalamine; antiemetics such as ondansetron,cyclizine, diphenyhydroamine, dimenhydrinate, meclizine, promethazine,and hydroxyzine; probiotic bacteria including but not limited tolactobacilli; lactase; racecadotril; and antiflatulents such aspolydimethylsiloxanes (e.g., dimethicone and simethicone, includingthose disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260);isomers thereof, and pharmaceutically acceptable salts and prodrugs(e.g., esters) thereof.

Examples of suitable analgesics, anti-inflammatories, and antipyreticsinclude, but are not limited to, non-steroidal anti-inflammatory drugs(NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen,ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen,fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and suprofen)and COX inhibitors such as celecoxib; acetaminophen; acetyl salicylicacid; acetic acid derivatives such as indomethacin, diclofenac,sulindac, and tolmetin; fenamic acid derivatives such as mefanamic acid,meclofenamic acid, and flufenamic acid; biphenylcarbodylic acidderivatives such as diflunisal and flufenisal; and oxicams such aspiroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof; andpharmaceutically acceptable salts and prodrugs thereof.

Examples of antihistamines and decongestants, include, but are notlimited to, bromopheniramine, chlorcyclizine, dexbrompheniramine,bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine,pripolidine, ephedrine, phenylephrine, pseudoephedrine,phenylpropanolamine, chlorpheniramine, dextromethorphan,diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine,naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine,clemastine, acrivastine, promethazine, oxomemazine, mequitazine,buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide,xylomeazoline, loratadine, desloratadine, and cetirizine; isomersthereof; and pharmaceutically acceptable salts and esters thereof.

Examples of cough suppressants and expectorants include, but are notlimited to, diphenhydramine, dextromethorphan, noscapine, clophedianol,menthol, benzonatate, ethylmorphone, codeine, acetylcysteine,carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, andguaifenesin; isomers thereof; and pharmaceutically acceptable salts andprodrugs thereof.

Examples of muscle relaxants include, but are not limited to,cyclobenzaprine and chlorzoxazone metaxalone, and orphenadrine,methocarbamol; isomers thereof; and pharmaceutically acceptable saltsand prodrugs thereof.

Examples of stimulants include, but are not limited to, caffeine.

Examples of sedatives include, but are not limited to sleep aids such asantihistiamines (e.g., diphenhydramine), eszopiclone, and zolpidem, andpharmaceutically acceptable salts and prodrugs thereof.

Examples of appetite suppressants include, but are not limited to,phenylpropanolamine, phentermine, and diethylcathinone, andpharmaceutically acceptable salts and prodrugs thereof

Examples of anesthetics (e.g., for the treatment of sore throat)include, but are not limited to dyclonene, benzocaine, and pectin andpharmaceutically acceptable salts and prodrugs thereof.

Examples of suitable statins include but are not limited to atorvastin,rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin,pravastatin and pharmaceutically acceptable salts and prodrugs thereof.

In one embodiment, the pharmaceutically active agent included within theorally disintegrative dosage formis selected from phenylephrine,dextromethorphan, pseudoephedrine, acetaminophen, ibuprofen, ketoprofen,loperamide, famotidine, calcium carbonate, simethicone, and menthol, andpharmaceutically acceptable salts and prodrugs thereof.

In one embodiment, the pharmaceutically active agent is selected fromphenylephrine, dextromethorphan, pseudoephedrine, chlorpheniramine,methocarbomal, chlophedianol, ascorbic acid, menthol, pectin, dyclonine,and benzocaine, and pharmaceutically acceptable salts and prodrugsthereof.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of pharmaceutically acceptablesalts, such as acidic/anionic or basic/cationic salts. Pharmaceuticallyacceptable acidic/anionic salts include, and are not limited to acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,pamoate, pantothenate, phosphate/diphospate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate and triethiodide. Pharmaceutically acceptablebasic/cationic salts include, and are not limited to aluminum,benzathine, calcium, chloroprocaine, choline, diethanolamine,ethylenediamine, lithium, magnesium, meglumine, potassium, procaine,sodium and zinc.

As discussed above, the pharmaceutically active agents of the presentinvention may also be present in the form of prodrugs of thepharmaceutically active agents. In general, such prodrugs will befunctional derivatives of the pharmaceutically active agent, which arereadily convertible in vivo into the required pharmaceutically activeagent. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, theinvention provides the esters, amides, and other protected orderivatized forms of the described compounds.

Where the pharmaceutically active agents according to this inventionhave at least one chiral center, they may accordingly exist asenantiomers. Where the pharmaceutically active agents possess two ormore chiral centers, they may additionally exist as diastereomers. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention. Furthermore, someof the crystalline forms for the pharmaceutically active agents mayexist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the pharmaceutically activeagents may form solvates with water (i.e., hydrates) or common organicsolvents, and such solvates are also intended to be encompassed withinthe scope of this invention.

In one embodiment, the pharmaceutically active agent or agents arepresent in the dosage form in a therapeutically effective amount, whichis an amount that produces the desired therapeutic response upon oraladministration and can be readily determined by one skilled in the art.In determining such amounts, the particular pharmaceutically activeagent being administered, the bioavailability characteristics of thepharmaceutically active agent, the dose regime, the age and weight ofthe patient, and other factors must be considered, as known in the art.

The pharmaceutically active agent may be present in various forms. Forexample, the pharmaceutically active agent may be dispersed at themolecular level, e.g. melted, within the dosage form, or may be in theform of particles, which in turn may be coated or uncoated. If thepharmaceutically active agent is in form of particles, the particles(whether coated or uncoated) typically have an average particle size offrom about 1 to about 2000 microns. In one embodiment, such particlesare crystals having an average particle size of from about 1 to about300 microns. In another embodiment, the particles are granules orpellets having an average particle size of from about 50 to about 2000microns, such as from about 50 to about 1000 microns, such as from about100 to about 800 microns.

If the pharmaceutically active agent has an objectionable taste, thepharmaceutically active agent may be coated with a taste maskingcoating, as known in the art. Examples of suitable taste maskingcoatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No. 5,489,436. Commercially available tastemasked pharmaceutically active agents may also be employed. For example,acetaminophen particles, which are encapsulated with ethylcellulose orother polymers by a coaccervation process, may be used in the presentinvention. Coaccervation-encapsulated acetaminophen may be purchasedcommercially from Eurand America, Inc. (Vandalia, Ohio) or from CircaInc. (Dayton, Ohio).

The pharmaceutically active agent may be present in pure crystal form orin a granulated form prior to the addition of the taste masking coating.Granulation techniques may be used to improve the flow characteristicsor particle size of the pharmaceutically active agents to make it moresuitable for compression or subsequent coating. Suitable binders formaking the granulation include but are not limited to starch,polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose,and hydroxypropylcellulose. The particles including pharmaceuticallyactive agent(s) may be made by cogranulating the pharmaceutically activeagent(s) with suitable substrate particles via any of the granulationmethods known in the art. Examples of such granulation method include,but are not limited to, high sheer wet granulation and fluid bedgranulation such as rotary fluid bed granulation, the details of whichare disclosed in, “The Theory and Practice of Industrial Pharmacy,3^(rd) edition”, Chapter 11, Lachman, Leon et. al, 1986.

As discussed above, one advantage of the orally disintegrating dosageform/portion described herein is the ability to incorporate modifiedparticles containing a pharmaceutically active agent, such astaste-masked particles, coated granules, or coated beads which aretypically sensitive to compression forces during manufacture.Traditional tablet compression can subject coated particles to forces,which can compromise the function of the coating (e.g., modifytaste-masking or modified release properties). In one embodiment theorally disintegrating form of this invention incorporates gel-coatedliquid filled beads, which may contain a flavorant, an active ingredientor mixtures thereof. In one embodiment the gel-filled beads are coatedwith materials that include, but not limited to, hydrocolloids (such asacacia, alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose,starches, and the like; and derivatives and mixtures thereof) and aplasticizer (such as propylene glycol, glycerin or mixtures thereof).Since, in one embodiment, the dosage form disclosed herein does notundergo a compression step, the gel-coated liquid filled beads are lesslikely break.

In one embodiment, the orally disintegrative dosage form/portionincorporates modified release coated particles (i.e., particlescontaining at least one pharmaceutically active agent that conveymodified release properties of such agent). As used herein, “modifiedrelease” shall apply to the altered release or dissolution of the activeagent in a dissolution medium, such as gastrointestinal fluids. Types ofmodified release include, but are not limited to, extended release ordelayed release. In general, modified release dosage forms areformulated to make the active agents(s) available over an extendedperiod of time after ingestion, which thereby allows for a reduction indosing frequency compared to the dosing of the same active agent(s) in aconventional dosage form. Modified release dosage forms also permit theuse of active agent combinations wherein the duration of one activeingredient may differ from the duration of another active ingredient. Inone embodiment the dosage form contains one pharmaceutically activeagent that is released in an immediate release manner and an additionalactive agent or a second portion of the same active agent as the firstthat is modified release.

In one embodiment the pharmaceutically active agent is coated with acombination of a water insoluble film forming polymer (such as but notlimited to cellulose acetate or ethylcellulose) and a water solublepolymer (such as but not limited to povidone, polymethacrylicco-polymers such as those sold under the tradename Eudragit E-100 fromRohm America, and hydroxypropylcellulose). In this embodiment, the ratioof water insoluble film forming polymer to water soluble polymer is fromabout 50 to about 95 percent of water insoluble polymer and from about 5to about 50 percent of water soluble polymer, and the weight percent ofthe coating by weight of the coated taste-masked particle is from about5 percent to about 40 percent.

In one embodiment one or more active ingredients or a portion of thepharmaceutically active agent may be bound to an ion exchange resin forthe purposes of taste-masking the pharmaceutically active agent ordelivering the active in a modified release manner.

In one embodiment, the pharmaceutically active agent is capable ofdissolution upon contact with a fluid such as water, stomach acid,intestinal fluid or the like. In one embodiment, the dissolutioncharacteristics of the pharmaceutically active agent within the orallydisintegrative dosage form meets USP specifications for immediaterelease tablets including the pharmaceutically active agent. Forexample, for acetaminophen tablets, USP 24 specifies that in pH 5.8phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least80% of the acetaminophen contained in the dosage form is releasedtherefrom within 30 minutes after dosing, and for ibuprofen tablets, USP24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2(paddles) at 50 rpm, at least 80% of the ibuprofen contained in thedosage form is released therefrom within 60 minutes after dosing. SeeUSP 24, 2000 Version, 19-20 and 856 (1999). In another embodiment, thedissolution characteristics of the pharmaceutically active agent aremodified: e.g. controlled, sustained, extended, retarded, prolonged,delayed and the like.

Effervescent Couple

In one embodiment, the orally disintegrative dosage form furtherincludes one or more effervescent couples. In one embodiment,effervescent couple includes one member from the group consisting ofsodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesiumcarbonate, sodium carbonate and one member selected from the groupconsisting of citric acid, malic acid, fumaric acid, tartaric acid,phosphoric acid, alginic acid.

In one embodiment, the combined amount of the effervescent couple(s) inthe orally disintegrative dosage form is from about 0.1 to about 20percent by weight, such as from about 2 to about 10 percent by weight ofthe total weight of the disintegrative dosage form.

Other Ingredients

The orally disintegrative dosage form may include other conventionalingredients, including other fillers, dry binders like polyvinylpyrrolidone and the like; sweeteners such as aspartame, acesulfamepotassium, sucralose, and saccharin; lubricants, such as magnesiumstearate, stearic acid, talc, and waxes; preservatives; flavors;disintegrants, antioxidants; acidulants, such as but not limited tocitric acid, malic acid, tartaric acid, ascorbic acid, and fumaric acid;surfactants; superdisinegrants; flavor and aroma agents; antioxidants;preservatives; texture enheancers; and coloring agents.

Examples of suitable sweeteners for use in the dosage form include, butare not limited to, synthetic or natural sugars, sucralose, saccarin,sodium saccarin, aspartame, acesulfame K or acesulfame, potassiumacesulfame, thaumatin, glycyrrhizin, dihydrochalcone, alitame,miraculin, monellin, stevside, and mixtures thereof.

Examples of superdisintegrants include but are not limited tocroscarmellose sodium, sodium starch glycolate and cross-linked povidone(crospovidone). In one embodiment the orally disintegrative form/portioncomprises up to about 5% by weight of such superdisintegrant.

Examples of suitable flavor and aroma agents include, but are notlimited to, essential oils including distillations, solvent extractions,or cold expressions of chopped flowers, leaves, peel or pulped wholefruit comprising mixtures of alcohols, esters, aldehydes and lactones;essences including either diluted solutions of essential oils, ormixtures of synthetic chemicals blended to match the natural flavour ofthe fruit (e.g., strawberry, raspberry and black currant); artificialand natural flavours of brews and liquors (e.g., cognac, whisky, rum,gin, sherry, port, and wine); tobacco, coffee, tea, cocoa, and mint;fruit juices including expelled juice from washed, scrubbed fruits suchas lemon, orange, and lime; mint; ginger; cinnamon; cacoe/cocoa;vanilla; liquorice; menthol; eucalyptus; aniseeds nuts (e.g., peanuts,coconuts, hazelnuts, chestnuts, walnuts, and colanuts); almonds;raisins; and powder, flour, or vegetable material parts includingtobacco plant parts (e.g., the genus Nicotiana in amounts notcontributing significantly to a level of therapeutic nicotine).

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts. Examples ofpreservatives include, but are not limited to, citric acid, tartaricacid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbicacid.

Examples of texture enhancers include, but are not limited to, pectin,polyethylene oxide, and carageenan. In one embodiment, texture enhancersare used at levels of from about 0.1% to about 10% percent by weight.

Disintegration Test

In one embodiment the orally disintegrating dosage form/portion meetsthe criteria for Orally Disintegrating Tablets as defined by the draftFood and Drug Administration guidance, as published in April 2007,incorporated herein by reference. In one embodiment the orallydisintegrating dosage form/portion of this invention meets a two-folddefinition for orally disintegrating tablets including the followingcriteria: 1) that the solid dosage form is one which contains medicinalsubstances and which disintegrates rapidly, usually within a matter ofseconds, when placed upon the tongue and 2) be considered a solid oralpreparation that disintegrates rapidly in the oral cavity, with anin-vitro disintegration time of approximately 30 seconds or less, whenbased on the United States Pharmacopeia (USP) disintegration test methodfor the specific medicinal substance or substances.

To determine the in-vitro disintegration for the dosage form, thedisintegration test for “Uncoated Tablets” according to USP30-NF25(using water as the immersion fluid) should be used. Briefly, one dosageunit is placed in each of the six tubes of the basket, and water(maintained at 37±2 C) is used as the immersion fluid. Thedisintegration time is determined by taking the greatest of sixmeasurements of the time period required to completely disintegrate therespective dosage form/portion. In one embodiment, the in-vitrodisintegration time of the orally disintegrative dosage form/portion isless than about 30 seconds, such as less than about 15 seconds.

In the embodiment wherein the orally disintegrative inner portion iscombined with an edible outer portion, the in-vitro disintegration timeof the outer edible outer portion is at least ten times, such as atleast 50 times or at least 100 times longer than the disintegration timeof the orally disintegrative portion.

Hardness Test

Hardness is a term used in the art to describe the diametral breakingstrength as measured by a Schleuniger Hardness Tester as described inLeiberman et al., Pharmaceutical Dosage Forms—Tablets, Volume 2, 2nded., Marcel Dekker Inc., 1990, pp. 213-217, 327-329. In order to performthe hardness test, a single dosage form/portion is placed into the steelchamber within the hardness tester, and the steel piston pushes againstthe dosage form until it breaks, measuring the force applied as ahardness measurement. In general, 5 dosage forms/portions are testedfrom any one sample in order to provide a mean hardness value inkiloponds. In one embodiment the dosage form has a hardness of less than5 kp/cm³, such as less than 2 kp/cm³, such as less than 1.5 kp/cm³.

An additional test for hardness of an orally disintegrating dosageform/portion of the present invention relies upon a Texture AnalyserTA-XT2i that is fitted with a 7 millimeter diameter flat faced probe andsetup to measure and report compression force in grams. The probe movesat 0.5 millimeters per second to a depth of penetration of 2millimeters. The maximum compression force is recorded. In oneembodiment, the measured forces recorded for orally disintegrativedosage forms/portions made in accordance with the present inventionpreferably ranges from approximately 700 grams to about 6000 grams, upto at most 10,000 grams.

In one embodiment the flowable material (e.g., the powder) is tampedslightly prior to the heating step. As the particle size of the hydrateis decreased following the tamping, less heat is needed to fuse theagglomerate to achieve the same hardness.

Manufacture and Packaging of Orally Disintegrative Dosage Form (a) UnitProduct Sheet

Pharmaceutical dosage forms, such as pills, capsules, tablets and thelike, may be packaged in unit product sheets, such as blister packages.In one embodiment, the blister package are comprised of multi-layeredsheets of material having pockets for containing the dosage forms.Conventional blister packages include packages having a foil layerthrough which a user of the package must push the tablet, breaking thefoil. U.S. Pat. No. 4,158,411 discusses such a blister package. Blistershaving open tops for containing pharmaceutical tablets are formed in aflexible sheet of plastic or aluminum material. An optional paperboardlayer having disc-shaped punch-outs covers the open tops of the blistersoverlying each dosage form. A foil layer covers the paperboard layer,holding the punch-outs in place. To open the package, the user mustcollapse the blister and push the tablet through the foil, also removingthe punch-outs.

Another type of blister package provides perforations between separableblister units so that the user can separate an individual dosage fromthe package prior to opening. U.S. Pat. No. 4,398,634 illustrates ablister package of this type. The blister portions are defined bytear-resistant, substantially planar plastic sheets sealed to oneanother in seal zones. The seal zones are located around the peripheryof each blister unit, forming pockets of unsealed areas which define theblisters, centrally located in the blister unit. Weakened areas in theseal zones allow the user to separate the blisters into individual unitsby tearing a unit away from the package. Upon separation of the unit,the user tears through the plastic layers, through the blister, to gainaccess to the dosage form. A slit in the corner of the unit is providedfor easy tearing.

Another type of blister package includes individual units that, uponseparation, reveal a tab for opening the blister. U.S. Pat. No.5,046,618 discloses this type of blister package. The blister package isformed from a sheet of material having blisters formed therein and asubstantially planar lidding sheet. This blister package has two rows ofblisters, each blister unit separated from an adjacent unit byperforations. Tear strips separate the rows with perforations that runbetween the tear strips and the blister units. To open the package, auser separates an individual unit from the package with a tear stripstill attached to the unit. This tear strip must be removed to accessthe tab, which comprises an unsealed area on the corner of the blisterunit. After the tear strip is removed, the user grabs the corner of thelidding sheet and peels the sheet back to reveal the dosage form.Suitable materials for constructing the blister cavity for use in theinvention described herein include, but are not limited to, polyvinylchloride (PVC), polyvinylidene chloride (PVDC), aluminum, andpolychlorotrifluoroethylene (PCTFE).

There are various production based machines which may be suitable formaking blister packaging, including the use of platen sealing such asthat made by the Uhlmann Packaging Systems company under model numberUPS4 and the use of rotary sealing such as that made by the BoschPackaging Group company in Minneapolis, Minn., USA. under model numberTLT 1400 and the TLT 2800.

The unit product sheet may be comprised of a sheet having one or aplurality of recesses (such as from about 2 to about 12, such as fromabout 2 to about 6) containing dosage forms arranged, for example, inrows and columns. The unit product sheet may includes a plurality ofunit packages, each unit package incorporating one recess and a sheetoverlying that recess. A set of tear lines can be included between theadjacent unit packages so that a user of the package may tear along thetear lines to separate a unit package.

The recesses of the package and the dosage forms disposed in therecesses may have essentially any shape. For example, the dosage formsmay be disk-shaped tablets, oblong capsules, square-shaped pills,hemispheres or truncated cones. Shapes for recesses include circular,oblong, polygonal, triangles or star shapes in the plane of the blistersheet.

Furthermore, the walls and bottom of the recesses may define a shape inthe form of a surface of revolution, about a vertical axis normal to theflange surrounding each of the recesses. For example, the recesses mayhave a curved, cup-like shape. Where the dosage forms are disc-shaped,they may each have an edge which contacts the walls of the recess inwhich each dosage form is disposed. The edge and walls define an annularregion of contact coaxial with the vertical axis of the recess. The edgeof such a disc-shaped dosage form may comprise a bevel, which contactsthe walls of the recess. The annular region of contact prevents shiftingof the dosage form within the blister and the damage to the dosage formassociated with such shifting. The unit product sheet must besubstantially deformable to allow for the punch out and removal of theorally disintegrating dosage form without breakage of the dosage form.The shape of the unit product sheet must also be such that the orallydisintegrating dosage form can be punched out and removed withoutbreakage of the dosage form. In one embodiment the (obtuse) angle of thebottom face of the blister to the angle of the side wall of the blisteris greater than 90° C., e.g. greater than 110° C.

(b) Manufacture Within Unit Product Sheets

The orally disintegrative dosage form may be made in a variety ofmethods. In one embodiment, the orally disintegrating dosage form ismade by a method comprising the steps of: (a) providing a unit productsheet having at least one recess in a desired shape and volume suitablefor containing the resulting orally disintegrating dosage form; (b)introducing into the recess a predetermined amount of a flowablematerial comprising at least about 5%, by weight, of at least onehydrated salt and a pharmaceutically active agent, wherein said at leastone hydrated salt has a dehydration temperature of from about 20 toabout 120° C.; (c) optionally, sealing the flowable material within therecess; (d) heating the material in the recess to a temperature abovesaid dehydration temperature for said at least one hydrated salt and fora sufficient period of time to cause the material to fuse into anaggregate, and (e) cooling the aggregate in the recess so that theaggregate solidifies into the orally dissolving dosage form suitable forconsumption.

In one embodiment a lubricant is added to the unit product sheet (e.g.,a blister package) prior to the addition of the flowable material. Thislubricant may be a liquid or solid, or integrated into the unit productsheet material. Suitable lubricants include but are not limited to solidlubricants such as magnesium stearate, starch, calcium stearate,aluminum stearate, talc, hydrogenated vegetable oil, sodium stearylfumarate, glyceryl behenate, and stearic acid; or liquid lubricants suchas but not limited to simethicone, lecithin, vegetable oil, olive oil,or mineral oil. In certain embodiments the lubricant is added at apercentage by weight of the orally disintegrating dosage form of lessthan 5 percent, e.g. less than 2 percent, e.g. less than 0.5 percent.

A flowable material, preferably in the form of a solid such as a powderor particulate agglomerate, is introduced into at least one of therecesses in the unit product sheet. In one embodiment the flowablematerial can be defined as one with an angle of repose of 20 to 44degrees. The angle of repose is defined by Terzaghi in “The TheoreticalSoil Mechanics in Engineering Practice”, Wiley, New York, 1948, as theangle between the horizontal and slope of a heap of soil (or powder)dropped from some elevation. In the embodiments of this invention it isdefined as the constant angle to the horizontal assumed by a cone likepile of material. This pile is built from a point above the horizontalusing two flat glass plates separated by at least ½ inch and whichallows for overflow.

The flowable material is preferably introduced into recesses that areprovided in product holding tray that can be a blister-type packagedescribed above. The materials in each unit are heated to a temperatureabove the dehydration temperature for the at least one hydrated salt andfor a sufficient period of time to cause the material to fuse into anaggregate, and resulting in a unitary dosage form suitable for handling,removal from the recess of the unit product sheet (such as a blister)and ingestion. In one embodiment, the other components remain solid andmaintain their physical properties, including hardness (e.g., thetemperature of the recess contents during the heating step should beabove the dehydration temperature, but below the melting points and thedecomposition temperatures of the other ingredients of the dosage form,including the pharmaceutically active agent). The time of heating isdependent on the at least one hydrated salt and the dimensions of theorally disintegrating form or portion, and must be sufficient inconjunction with the temperature to fuse and stabilize the agglomerateform. In certain cases the active ingredient may be temperaturesensitive, requiring different minimal heating temperature with a longerheating time.

Suitable heat sources include a radiant heater, conductive heating,convective heating, radiofrequency heating, sonic heating, microwaveheating, or laser. In one embodiment, the temperature and time ofcooling are such as to bridge the carbohydrate or carbohydrate granuleswith the hydrate salt, creating a soldified dosage form. In oneembodiment, a portion of the carbohydrate (e.g., carbohydrate granules)dissolves under release of the water from the hydrated salt and then,upon recrystallization, forms bridged crystalline structures at amicroscopic level. In one embodiment, the temperature during cooling isabout 25° C. to about 0° C., and the time of cooling is about 10 toabout 60 seconds. Generally, the higher the temperature during cooling,the longer the cooling time. In one embodiment the cooling takes placeat room temperature (25° C.) for greater than 5 minutes.

(c) Manufacture Within an Edible Outer Portion

The orally disintegrating dosage form may also be incorporated within aseparate edible outer portion, such as a hard candy. In one embodiment,the hard candy portion is a sugar glass hard candy formed from bycooling boiled sugar candy. In another embodiment, the hard candyportion is a compressed sugar candy made by compression, with a hardnessof at least 15 kiloponds, such as at least 20 kilponds. In oneembodiment, an edible outer portion is pre-made prior to the addition ofthe orally disintegrating dosage form. In one such embodiment, an outerhard candy or compressed candy ring is manufactured as an edible outerportion, the fixed amount of flowable material containing at least oneactive ingredient is added, and the dosage form is heated for thetemperatures and times described above to form an orally disintegratingtablet portion within the dosage form, and subsequently packaged into ablister, pouch or bottle. In one embodiment, the edible outer portion issubstantially enclosed in order to hold the material for the heating orfusing step. In these embodiments, substantially enclosed can beachieved by forming a ring, an oval or other shape such as but notlimited to a triangle, star, moon, etc. with an internal hollow portionsufficient to hold the material. This form is placed onto a surface inorder to hold the material. This surface may be suitable for holding anyflat shape including but not limited to plastic, metal, or composite.This may also be achieved within a preformed unit product sheet and mayhave negative embossing in order to transfer a logo, image or productidentification upon heating and fusing of the dosage form.Alternatively, the dosage form may be lasered or printed for aestheticimaging (shapes, characters, colors, etc.) or identification (productname, dosage, etc.).

In one embodiment, the outer hard candy form is made using uniplastrolling, roping and subsequent cutting and stamping, as well asdepositing into molds. In one embodiment, the hard candy portioncontains one or more sugars selected from the group consisting ofisomalt, sucrose, dextrose, corn syrup, lactitol, and hydrogenatedstarch hydrolysates. In one embodiment, the hard candy portion containsat least 50% (such as at least 75%, such as at least 90%) by weight ofsuch sugar(s).

In one embodiment, the dosage form comprising an edible outer portionand an inner orally disintegrating portion is coated with an immediaterelease sugar coating or film coating. To produce such a dosage form,the step following the fusing (heating) and subsequent cooling of thedosage form would involve further sugar or film coating in a coatingpan.

In one embodiment the edible outer portion contains a pharmaceuticallyactive agent and the orally disintegrating portion contains the samepharmaceutically active agent. In one embodiment the edible outerportion contains a pharmaceutically active agent and the orallydisintegrating dosage form contains a different pharmaceutically activeagent. In one embodiment the edible outer portion disintegrates at arate of at least 10 times greater than the rate of the orallydisintegrating dosage form portion, such as at least 20 times greater.In one embodiment, the orally disintegrating portion meets the FDArequirements for Orally Disintegrating Tablets. In one embodiment theorally disintegrating portion contains an upper respiratorypharmaceutically active agent such as pseudoephedrine, dextromethorphan,cetirizine, diphenhydramine, and chlorpheniramine and the edible outerportion contains menthol.

Use of Orally Disintegrative Dosage Form

In one embodiment, the present invention features a method of treatingan ailment, the method comprising orally administering the abovedescribed dosage form wherein the dosage form includes an amount of thepharmaceutically active agent effective to treat the ailment. Examplesof such ailments include, but are not limited to, pain (such asheadaches, migraines, sore throat, cramps, back aches and muscle aches),fever, inflammation, upper respiratory disorders (such as cough andcongestion), infections (such as bacterial and viral infections),depression, diabetes, obesity, cardiovascular disorders (such as highcholesterol, triglycerides, and blood pressure), gastrointestinaldisorders (such as nausea, diarrhea, irritable bowel syndrome and gas),sleep disorders, osteoporosis, and nicotine dependence.

In one embodiment, the method is for the treatment of an upperrespiratory disorder, wherein the pharmaceutically active agent isselected from the group of phenylephrine, cetirizine, loratidine,fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine,chlophedianol, and pseudoephedrine.

EXAMPLES

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples.

Example 1 Orally Disintegrating Immediate Release Loratidine TabletBlend (a) Cold Forming of Blister Packaging

Using a Bosch TLT 1400 (rotary thermoforming sealing) blister linemachine, a web of aluminum blister forming material is unwound from aroll, and then indexed into the forming station where compressed airand/or a vacuum is used to form cavities in the web at a ⅝ inch flatround cavity with depressions containing the product's tradename as anidentifier to produce a thermoformed web.

The resulting thermoformed web is indexed into a feeder station wherethe tablet blend formulation described below in Example 2 are depositedinto the formed cavities.

(b) Tablet Blend Formulation

An orally disintegrating immediate release loratidine tablet blendformulation including the ingredients of Table 1 is manufactured asfollows:

TABLE 1 Granulation Blend G/Batch Mg/Tablet Dextrose 87.71 1052.5Monohydrate Sodium Hydrogen 9.74 116.9 Phosphate Hydrate* Sucralose USP0.60 7.2 Flavor 1.12 13.4 Loratidine 0.83 10.0 Total 100.0 1200.0*Chemical formula: Na₂HPO₄•7H₂O

Dextrose Monohydrate, sucralose and flavor are screened through a 30mesh screen and placed into a 500 cc plastic bottle and mixedend-over-end for 5 minutes. The loratidine and sodium hydrogen phosphatehydrate are added and blended end over end for an additional 3 minutes.The blend is then filled into the pre-formed blister cavities in Example1.

(c) Packaging of Blisters

Blister forming pins or punches, used to pre-form the blister cavitiesprior to addition of the flowable material, contain small injectionports which inject approximately about 0.1-5 mg of soy lecithin onto thesurface of the blister upon forming the cavity, in order to facilitateejection of the blend formulation. The formed blister material fromExample 1 is then indexed into a seal station where a foil lidding isapplied. The lidding material is unwound from a roll and sealed togetherusing heat and mechanical pressure resulting in the product beingcontained within the cavity. The sealed blister is placed into aconvection oven set at 55° C. for 15 minutes

The sealed web is indexed toward the perforating station. Theperforating station uses sharp cutting blades to place perforationsthrough the web resulting in a blister card with an opening feature.Lastly, the web moves to the punch station where individual blister arecut from the web into individual cards containing 6 orallydisintegrating forms per card.

The blister cavity is then cooled at 0° C. for 5 minutes and sealed. Thetablets are then removed from the blister cavity as a single dosage unitfor ingestion.

Example 2 Preparation of Outer Edible Ring Portion with Fused OrallyDisintegrating Tablet Inner Portion (a) Preparation of an Edible OuterRing Portion

All materials set forth in Table 2 below are manually passed through a30 mesh screen. One and a half (1.5) kg of the resulting blend areplaced in a 4 quart V-Blender and mixed for 5 minutes.

TABLE 2 Weight Percent Ingredients (w/w) Weight (mg) Sorbitol 5 50Compressible Sucrose* 92.75 927.5 Menthol 1 10 Peppermint Flavor 0.5 5Magnesium Stearate 0.75 7.5 TOTAL 100 1000 *Commercially available fromDomino Specialty Ingredients, Baltimore, MDFour hundred (400) g of the resulting blend is then removed from theblender and compressed on a rotary tablet press at 60 rpm using ¾″ringed tablet tooling in order to yield flat faced rings having ½″ emptycenters and having a weight of 1000 mg and a hardness range of not lessthan 15 kp/cm², and a thickness of about 0.20 inches.

(b) Preparation of Inner Orally Disintegrating Portion

An orally disintegrating immediate release loratidine tablet blendformulation including the ingredients of Table 3 is manufactured asfollows:

TABLE 3 Granulation Blend G/Batch Mg/Tablet Dextrose 86.67 433.3Monohydrate Sodium Hydrogen 9.62 48.1 Phosphate Hydrate* Sucralose USP0.6 3 Flavor 1.12 5.6 Loratidine 2 10 Total 100 500 *Na₂HPO₄•7H₂O

Dextrose Monohydrate, sucralose and flavor are screened through a 30mesh screen and placed into a 500 cc plastic bottle and mixedend-over-end for 5 minutes. The loratidine and sodium hydrogen phosphatehydrate are added and blended end over end for an additional 3 minutes.

(c) Preparation of Edible Outer Ring Portion with Fused OrallyDisintegrating Tablet Inner Portion

The edible outer ring portion from part (a) is placed into a formedblister cavity. 500 mg of the blend from part (b) is then filled intohole in the ring, and the blister is sealed. The sealed blister isplaced into a Convection Oven set at 55° C. for 15 minutes. The blistercavity is then cooled at 0° C. for 5 minutes. The dosage forms are thenremoved from the blister cavity as a single dosage unit for ingestion.

It is understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the claims.

1. An orally disintegrating dosage form comprising from about 5% toabout 40%, by weight, of at least one hydrated salt and apharmaceutically active agent, wherein said at least hydrated salt has adehydration temperature of from about 20 to about 120° C.
 2. The orallydisintegrating dosage form of claim 1, wherein said orallydisintegrating dosage form has a in-vitro disintegration time of lessthan thirty seconds.
 3. The orally disintegrating dosage form of claim1, wherein said orally disintegrating dosage form further comprises atleast 40%, by weight, of at least one carbohydrate.
 4. The orallydisintegrating dosage form of claim 3, wherein said at least onecarbohydrate is selected from the group consisting of dextrose, dextrosemonohydrate, lactose, glucose, fructose, isomalt, sucrose, mannose,maltose, maltodextrin, corn syrup solids, hydrogenated starchhydrolysates, lactitol, xylitol, mannitol, erythritol, and sorbitol, andmixtures thereof.
 5. The orally disintegrating dosage form of claim 3,wherein the weight ratio of said at least one hydrated salt to said atleast one carbohydrate is from about 1:4 to about 1:30.
 6. The orallydisintegrating dosage form of claim 1, wherein said at least onehydrated salt is selected from the group consisting of sodium sulfatehydrate, sodium carbonate hydrate, calcium chloride hydrate, sodiumhydrogen phosphate hydrate, and mixtures thereof.
 7. An orallydisintegrating dosage form of claim 1, wherein said orallydisintegrating dosage form has a hardness of less than 5 kp/cm³.
 8. Anorally disintegrating dosage form of claim 1, wherein saidpharmaceutically active agent is selected from the group consisting ofacetaminophen, ibuprofen, ketoprofen, loperamide, famotidine,cetirizine, phenylephrine, dextromethorphan, calcium carbonate, ascorbicacid, and diphenyhydramine.
 9. An orally disintegrating dosage form ofclaim 1 comprising gel-coated liquid filled beads.
 10. A process formaking an orally disintegrating dosage form, said method comprising thesteps of: a) providing a unit product sheet having a recess in a desiredshape and volume suitable for containing said orally disintegratingdosage form; b) introducing into the recess a predetermined amount of aflowable material comprising at least about 5%, by weight, of at leastone hydrated salt and a pharmaceutically active agent, wherein said atleast one hydrated salt has a dehydration temperature of from about 20to about 120° C.; c) heating the material in the recess to a temperatureabove said dehydration temperature for said at least one hydrated saltand for a sufficient period of time to cause the material to fuse intoan aggregate, and d) cooling the aggregate in the recess so that theaggregate solidifies into the orally dissolving dosage form suitable forconsumption.
 11. The process of claim 10, wherein the unit product sheetis a blister-type package.
 12. The process of claim 10, wherein the heatis applied via convection, conduction, sonic heating, radiofrequency,laser, infrared, or microwave.
 13. The process of claim 10, wherein therecess has positive imprinted portions on its interior surface and whichproduce corresponding patterns in the final dosage form.
 14. The processof claim 10, wherein said process further comprises the step of sealingthe flowable material within the recess prior to said heating step (c).15. A dosage form comprising an edible outer portion and an orallydisintegrating portion, said edible outer portion containing the orallydisintegrating portion of said dosage form and said orallydisintegrating portion comprising at least about 5%, by weight, of atleast one hydrated salt and a pharmaceutically active agent, whereinsaid at least one hydrated salt has a dehydration temperature of fromabout 20 to about 120° C.
 16. A dosage form of claim 15, wherein saidedible outer portion comprises a pharmaceutically active agent
 17. Adosage form of claim 15, wherein said edible outer portion is a hardcandy
 18. A process for making a dosage form comprising an edible outerportion and an orally disintegrating portion, said method comprising thesteps of: a) preparing an edible outer portion having a recess in adesired shape and volume suitable for containing the orallydisintegrating portion of said dosage form; b) introducing into therecess a predetermined amount of a flowable material comprising at leastabout 5%, by weight, of at least one hydrated salt and apharmaceutically active agent, wherein said at least one hydrated salthas a dehydration temperature of from about 20 to about 120° C.; c)heating the material in the recess to a temperature above saiddehydration temperature for said at least one hydrated salt and for asufficient period of time to cause the material to fuse into anaggregate, and d) cooling the aggregate in the recess so that theaggregate solidifies into the orally dissolving dosage form suitable forconsumption.
 19. The process of claim 18 wherein the edible outerportion is prepared via compression.
 20. The process of claim 18 whereinthe edible outer portion is a outer hard candy form prepared by a methodselected from the group consisting of uniplast rolling, roping andsubsequent cutting and stamping, or mold depositing.